Post-Transplant Complications

Characterization and management of hypercalcemia following transplantation for osteopetrosis

Abstract

Autosomal recessive osteopetrosis (OP) is characterized by insufficient osteoclast activity resulting in defective bone resorption and marked increase in skeletal mass and density. OP has been successfully treated with hematopoietic cell transplantation (HCT), secondary to engraftment of donor-derived functioning osteoclasts resulting in remodeling of bone and establishment of normal hematopoiesis. Although hypercalcemia is a common presenting feature of OP, it may be observed following HCT due to engraftment of osteoclasts differentiated from the hematopoietic precursors. To characterize hypercalcemia after HCT—who is at risk, onset, duration and response to treatment—we evaluated 15 patients with OP treated at the University of Minnesota from 2000 to 2009. Hypercalcemia, defined as any single calcium >11.0 mg/100 ml after the first transplant, was found in 40% of patients. Median onset of hypercalcemia was 23 days and the duration was 2–24 days. Hypercalcemia was more common in patients older than 2 years of age at the time of HCT. Treatment with hydration, furosemide and s.c. calcitonin resolved hypercalcemia and resulted in no severe adverse events. In conclusion, hypercalcemia is common in patients with OP within the first 4 weeks after HCT, and more likely in older patients. Isotonic saline, furosemide and s.c. calcitonin were well-tolerated and effective treatments in our study population.

Introduction

Autosomal recessive osteopetrosis (OP) is a rare inherited condition characterized by insufficient osteoclast activity resulting in defective bone resorption and a marked increase in bone mass. The majority of children with OP have mutations in the osteoclast-specific H+-ATPase proton pump A3 subunit (TCIRG1), whereas the second most common genotype is associated with recessive mutations in the chloride channel gene, ClCN7.1, 2 The deposition of bone by osteoblasts without balanced resorption by osteoclasts results in increased bone mass with markedly abnormal architecture of the marrow space, leading to progressive marrow failure and compensatory extramedullary hematopoiesis.3, 4 Affected children may present with a variety of signs and symptoms within the first year of life, including hypocalcemic seizures, macrocephaly, hydrocephaly, cranial nerve deficits leading to blindness or deafness, choanal atresia, micrognathia, small thorax, hepatosplenomegaly and failure to thrive.

A variety of medical interventions have been attempted, including high-dose calcitriol, parathyroid hormone (PTH), steroids, interferon and macrophage CSF, but efficacy has been variable and, at best, transient.5, 6, 7, 8 Without curative therapy the severe or ‘malignant’ form of OP is usually fatal within the first decade of life, and the milder forms may still result in significant morbidity by early adulthood. Currently, the only known cure is allogeneic hematopoietic stem cell transplantation (HCT). Successful HCT leads to engraftment of donor-derived functioning osteoclasts, resulting in bony remodeling and establishment of normal hematopoiesis, and possibly limiting other complications such as visual compromise.9, 10, 11, 12, 13

However, in children with OP, HCT has been associated with a high incidence of adverse outcomes, especially when alternative stem cell sources are used. Common adverse outcomes have been difficulty in achieving sustained donor engraftment, early transplant mortality from sepsis and complications such as pulmonary hypertension, airway and respiratory failure, and hypercalcemia.9, 11, 13, 14 Diagnosis and treatment of hypercalcemia are clinically important because of the associated morbidity, including nephrolithiasis, nausea/vomiting, polyuria and dehydration, altered mental status, coma and ultimately cardiac arrest and death.

Hypercalcemia after HCT has been documented in some case reports of patients with OP treated with HCT.11, 15, 16, 17 The prevalence of hypercalcemia in this population has been reported to be between 16 and 24%, and to be more common in patients more than 2 years of age at the time of HCT.11, 17 Other risk factors for hypercalcemia after HCT and the most appropriate treatment options have not been clearly defined. Given these uncertainties, we performed a single-center, retrospective review of patients with OP after treatment with HCT at the University of Minnesota. In this paper, we describe the prevalence, timing and duration of hypercalcemia in patients with OP after HCT, examine some potential risk factors for developing hypercalcemia, and discuss the risks and benefits of hypercalcemia treatment options in this unique population.

Patients and methods

Patients

All 15 patients who were treated for OP with HCT at the University of Minnesota between 2000 and 2009 were included. No exclusions were made. Data were collected from the electronic medical record as well as from the University of Minnesota Bone Marrow Transplant Database that prospectively collects standard data on patients. The diagnosis of OP was made clinically. Tolar et al.9 reported overall survival, engraftment and transplant-related mortality in these patients except for patient five. Four patients with ‘intermediate’ OP were treated as adults in an attempt to improve their quality of life by arresting the progressive nature of their disease that could not be effectively managed with other interventions. These complications included persistent infections, repeated disabling fractures and in some cases hematopoietic deterioration.

HCT procedures

Patients were transplanted according to institutional review board-approved protocols, and informed consent was obtained in all cases. The preparative regimen consisted of BU 2 mg/kg over 2 consecutive days (total dose 8 mg/kg), fludarabine 35 mg/m2 once daily i.v. (total dose 175 mg/m2), horse antithymocyte globulin 30 mg/kg (total dose 150 mg/kg), along with total lymphoid and abdominal irradiation of 500 cGy delivered as a single fraction to include the liver and spleen in the radiation field in 9 out of 15 patients. Five patients received a preparatory regimen of Campath 0.3 mg/kg daily i.v. for 5 consecutive days (total dose 1.5 mg/kg), CY 50 mg/kg for 2 days (total dose 100 mg/kg), fludarabine 35 mg/m2 for 5 days (total dose 175 mg/m2), melphalan 140 mg/m2 and TBI (for marrow and matched related or unrelated PBSC arm). Two of these patients received a CD34-selected product. Three patient received Campath 0.3 mg/kg daily i.v. for 5 consecutive days (total dose 1.5 mg/kg), CY 50 mg/kg for 2 days (total dose 100 mg/kg), fludarabine 35 mg/m2 for 5 days (total dose 175 mg/m2), melphalan 140 mg/m2 and TBI (for matched related or unrelated PBSC arm). One patient received Campath 0.3 mg/kg daily i.v. for 5 consecutive days (total dose 1.5 mg/kg), CY 50 mg/kg for 2 days (total dose 100 mg/kg), clofarabine 40 mg/m2 for 5 days (total dose 200 mg/m2), melphalan 140 mg/m2 and TBI. CsA and mycophenolate mofetil were used as prophylaxis for acute GVHD (for umbilical cord blood (UCB) arm).

BM and PBSC grafts were matched at the allele level for class I and II, whereas testing at the antigen level was considered in choosing unrelated cord blood units at class I, with allele level testing used for cord blood at class II. Thirteen patients received a single transplant, one patient required a second HCT following graft failure (patient 14) and one patient received three transplants (patient 15). This patient received his second transplant on day +221 following his first transplant, and the third transplant was given 60 days later. Hematopoietic engraftment was defined as donor chimerism >75% at day 100 assessed on peripheral blood leukocyte DNA by competitive PCR analysis of variable tandem repeat regions. The donor grafts consisted of unrelated BM (n=5), related BM (n=1), unrelated UCB (n=4), related PBSCs (n=2) and unrelated PBSCs (n=3). Myeloid recovery was defined as an absolute neutrophil count of >0.5 × 109 cells per liter for 3 consecutive days, and platelet engraftment was defined as maintaining an untransfused platelet count >50 × 109 cells per liter for 7 consecutive days.

Hypercalcemia

Calcium levels were evaluated at multiple time points during HCT process, beginning on admission, before engraftment and following throughout myeloid recovery. Hypercalcemia was defined as any single calcium >11.0 mg/100 ml after the first transplant. Hypercalcemia was managed with i.v. fluids, furosemide diuresis and calcitonin when refractory to fluids and diuretic therapy.

Statistical analysis

Owing to the small patient numbers in this study, analysis was primarily descriptive but statistical comparisons were carried out by the following statistical tests: correlations between calcium levels and age, type of donor graft, HLA matching, total nucleated count of the graft, CD34+ cell dose, timing of myeloid recovery and donor chimerism were evaluated by use of a standard t-test for normalized continuous variables by categorical data and Fisher's exact test for categorical data alone. Correlations between two continuous factors were evaluated by Spearman's rank correlation. All P-values of 0.05 or less were considered indicative of statistical significance.

Results

Patients

The characteristics of the 15 patients reviewed in this study and their grafts, as well as transplant outcomes, are summarized in Table 1. The median age at HCT was 1 year (range 0.3–36.5 years). The indication for second HCT was loss of donor chimerism, and there was an interval of 5 months (patient 14) and 7 months (patient 15), between their first and second transplants.

Table 1 Patient and transplant characteristics and outcomes

HCT procedures

Donor engraftment (defined as donor chimerism of more than 75%) was observed in nine patients after the first transplant (Table 1). Of these, five received a BM, three PBSC grafts and one a UCB graft. One patient (patient 14) developed autologous reconstitution and required another unrelated donor (URD) PBSC transplant and three previously stored PBSC infusions to achieve engraftment. One patient (patient 15) developed autologous reconstitution and required two further transplants (URD BM followed by a UCB graft). Overall, two recipients of UCB grafts (patients 2 and 15), one of PBSC graft (patient 14) and one of URD BM graft (patient 8) had transient partial engraftment followed by autologous recovery. The median day of myeloid recovery was day 17 (range 12–23 days). The median day of myeloid recovery in the hypercalcemia and without hypercalcemia groups was 14 and 17, respectively (Tables 2 and 3). Of the five patients who did not achieve engraftment by day 100, maximum donor engraftment was achieved as follows: patient 2, 1–25% at day 21; patient 8, 91% at day 25; patient 9, 100% at day 21 (died before day 100); patient 10, 84% at day 30 (died before day 100); patient 14, 84% at day 26 (first graft) and 100% at day 60 (second graft); patient 15, 33% at day 21 (first graft), 14% at day 21 (second graft) and 65% at day 21 (third graft).

Table 2 OP patients with hypercalcemia
Table 3 OP patients without hypercalcemia

The causes of death included severe GVHD with pulmonary and intracranial hemorrhage (patient 1), sepsis (patients 5 and 9), refractory autoimmune hemolytic anemia 7 months after HCT (patient 6), GVHD and liver disease (patient 14), respiratory failure, graft failure and sepsis (patient 15), and sudden respiratory arrest of uncertain etiology at home (no autopsy was performed) two-and-a-half years after autologous reconstitution (patient 2). Although this respiratory arrest was thought to be due to upper-airway-related issues, this cannot be confirmed. Three of the six (50%) patients with hypercalcemia died, compared to five of nine (56%) patients without hypercalcemia.

Hypercalcemia

Hypercalcemia after HCT was found in 6 of the 15 patients (40%; Table 2). The median day of onset of hypercalcemia was 23.5 days (range 14–67 days). Hypercalcemia lasted for 2–24 days (median 10.5 days). Four of the six (67%) patients with hypercalcemia were young adults, whereas the patients who did not develop hypercalcemia were significantly (P=0.03) younger (age 0.3–4.5 years). Hypercalcemia after HCT was seen in 67% of the patients more than 2 years old, whereas hypercalcemia was observed in only 22% of the patients younger than 2 years of age. In patients who received PBSC, 40% developed hypercalcemia, for UCB 50% and for BM 33% developed hypercalcemia.

Of the patients who developed hypercalcemia, patients 2 and 3 were treated with i.v. fluids and were taking furosemide for fluid retention. Patients 5, 12 and 13 (all adults) had persistent hypercalcemia with i.v. hydration and furosemide; therefore s.c. calcitonin was added. For patient 5, calcitonin was started at 100 IU s.c. every 12 h on the day of peak calcium (day +31), increased to 200 IU s.c. every 12 h after 24 h then discontinued after 4 days in response to a serum calcium of less than 13 mg/100 ml. Hypercalcemia persisted for an additional 11 days. Patient 12 was treated with calcitonin 300 IU s.c. every 12 h for 3 days, also initiated at the day of peak calcium (day +34). It was discontinued after calcium was less than 12 mg/100 ml for 48 h. Hypercalcemia persisted for an additional 10 days. Patient 13 was treated with s.c. calcitonin for 14 days; starting dose was 200 IU s.c. every 12 h. This was then increased after 2 days to 200 IU s.c. every 8 h because of persistent hypercalcemia. He was maintained on this dose for 4 days at which time calcitonin was discontinued for 24 h due to the development of a rash. The rash did not improve calcitonin, and hypercalcemia worsened; therefore calcitonin was restarted at 200 IU s.c. every 12 h. Calcitonin was discontinued 6 days later when serum calcium was less than 10.4 mg/100 ml for 2 consecutive days. Hypercalcemia did not recur. There were no adverse effects during treatment that were thought to be related to calcitonin.

The mean peak calcium level of patients with hypercalcemia was 13.1 mg/100 ml compared to 9.9 mg/100 ml in the patients without hypercalcemia (P<0.01). The serum calcium levels during the time of myeloid recovery were significantly higher in patients with hypercalcemia (P=0.02). The mean day of peak calcium levels in patients with hypercalcemia was day 37.2, in contrast to day 21.4 in patients who did not develop hypercalcemia (P=0.06). The peak calcium levels in the whole group of patients did not correlate with time of neutrophil engraftment (P=0.94). There was no correlation found between hypercalcemia and the type of donor graft, cell dose, HLA match or number of transplants.

Discussion

In this report, we have shown an estimated prevalence of hypercalcemia in patients with OP after HCT of 40% (67% of the patients more than 2 years old and 22% of the patients younger than 2 years of age), an onset of hypercalcemia between days 14 and 27 (onset in one patient was not until day 67) after HCT and duration of 2–24 days (median 10.5 days). Hypercalcemia was successfully and safely treated with i.v. fluids, furosemide dieresis and calcitonin.

The time after HCT to peak calcium level was earlier in those who did not develop hypercalcemia compared to those who were hypercalcemic after HCT. A shorter time to engraftment was not associated with likelihood of hypercalcemia. However, calcium levels were significantly higher at the time of myeloid recovery in those who went on to develop hypercalcemia compared to those who did not. The only risk factor identified was a younger age at HCT. Combined, these data suggest a microenvironment renewal by donor-derived osteoclasts resulting in an increased release of calcium stored in the osteopetrotic bones, with a larger bone mass in older patients resulting in more significant hypercalcemia.

Identification and treatment of hypercalcemia is critical due to the adverse effects of hypercalcemia including nephrolithiasis, nausea/vomiting, polyuria, altered mental status, coma and ultimately cardiac arrest. Hypercalcemia has been reported in patients with OP after HCT. Gerritsen et al.11 published a report on 69 patients with OP treated with HCT between 1974 and 1994 in Europe; they found that 24% of those with successful engraftment developed hypercalcemia, and similar to our study, that hypercalcemia was more likely in patients who were older than 2 years at the time of HCT. A later study by Dreissen et al.17 and Gerritsen et al.11 reported a prevalence of 16% in all OP patients treated with HCT and also found that those transplanted when older than 2 years of age were more likely to develop hypercalcemia. Our prevalence data are slightly higher. This is likely because we had six patients older than 2 year of age at the time of transplant, four of whom were adults at the time of transplant. Our data do confirm the previous findings of an increased risk for hypercalcemia if the age at HCT is more than 2 years.

Dini et al.16 reported hypercalcemia in two patients, ages 5 and 12 years, treated for OP with HCT. Hypercalcemia was treated with a combination of a bisphosphonate, phosphate infusions, vigorous hydration and calcitonin. Rawlinson et al.15 have reported severe hypercalcemia in a 3-year-old girl treated with HCT for OP, whose hypercalcemia was also treated with a combination of a bisphosphonate, phosphate infusions, vigorous hydration and calcitonin. In our study, three patients with hypercalcemia required only vigorous hydration and a loop diuretic; three patients required more aggressive treatment for which we chose calcitonin, and bisphosphonates were never used.

There are various treatment options for hypercalcemia—hydration, loop diuretic, glucocorticoids, calcitonin or bisphosphonates. The most benign of these is hydration and a loop diuretic if required. However, hydration and furosemide are not always sufficient for the treatment of hypercalcemia in this population. The decision regarding when further treatment is required is difficult and needs to be balanced between the need to treat symptomatic hypercalcemia and the goal of achieving continued bone remodeling by healthy, donor osteoclasts. Glucocorticoids, calcitonin and bisphosphonates have all been used in the treatment of hypercalcemia. We have chosen to use calcitonin because it has the shortest duration of action, is a weak inhibitor of osteoclast activity, is less likely to cause apoptosis of osteoclasts and because it increases renal excretion of calcium by antagonizing the action of PTH at the kidney.18, 19 Bisphosphonates block bone resorption and cause osteoclast apoptosis, effects that may continue up to 1–2 years after treatment.20, 21, 22 Glucocorticoids mainly exert an effect to decrease calcium levels by decreasing intestinal absorption of calcium. Glucocorticoids reduce 1,25-dihydroxyvitamin D levels and are mostly effective in treating hypercalcemia associated with high 1,25-dihydroxy vitamin D levels, for example in granulomatous diseases and multiple myeloma,23, 24, 25 but less effective in the treatment of hypercalcemia in OP after HCT compared with other treatment options discussed.

On the basis of these data, we hypothesize that calcitonin should have the least negative impact on critical bone remodeling and overall engraftment compared with glucocorticoids or bisphosphonates. There were no serious adverse events related to the use of calcitonin, and hypercalcemia was effectively treated. Unfortunately, there are no long-term studies evaluating graft outcomes in patients with OP after HCT who were treated with either calcitonin or bisphosphonates for severe hypercalcemia. Until data are available, the safest treatment for hypercalcemia in this population, after hydration and diuretics, remains unknown.

In summary, we describe the prevalence, onset and duration of hypercalcemia in patients with OP after HCT. On the basis of our findings, we recommend close monitoring of calcium levels, particularly in the first 4 weeks after stem cell infusion and initiation of treatment of hypercalcemia for levels above 11 mg/100 ml or less if symptomatic. Hydration with isotonic saline is the first-line therapy, followed by the addition of a loop diuretic. If hypercalcemia persists, then our recommendation based on the currently available data is to add s.c. calcitonin for more aggressive treatment of persistent hypercalcemia. The function of bisphosphonates in patients with OP remains uncertain. Further studies are needed to determine the safest and most effective treatment choices for the treatment of hypercalcemia in this unique population.

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Acknowledgements

This publication was supported by NIH/NCRR Grant number K12 RR023247. Its contents are the authors' sole responsibility and do not necessarily represent official NIH views. This work was supported in part by the Children's Cancer Research Fund and the Bone Marrow Transplant Research Fund.

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Correspondence to C Martinez.

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The authors declare no conflict of interest. No honorarium, grant or other form of payment was given to authors to produce the paper.

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Martinez, C., Polgreen, L., DeFor, T. et al. Characterization and management of hypercalcemia following transplantation for osteopetrosis. Bone Marrow Transplant 45, 939–944 (2010). https://doi.org/10.1038/bmt.2009.277

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Keywords

  • osteopetrosis
  • hypercalcemia
  • hematopoietic stem cell transplantation
  • calcitonin

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